Novel Kinases Which Phosphorylate Proteins And Proteoglycans In The Secretory Pathway

Protein phosphorylation is a fundamental mechanism regulating nearly every aspect of life. Several secreted proteins are phosphorylated, but the kinases responsible are unknown. We identified a family of atypical protein kinases which have N-terminal signal sequence and localize to the lumen of the endoplasmic reticulum and the Golgi apparatus. One of these kinases known as Fam20C is the Golgi casein kinase and it phosphorylates secretory pathway proteins within S-x-E motifs. Fam20C phosphorylates the caseins and many other secretory proteins including the small integrin-binding ligand, N-linked glycoproteins (SIBLINGs) implicated in biomineralization. Consequently, mutations in Fam20C cause an osteosclerotic bone dysplasia in humans known as Raine syndrome. Another family member, Fam20B, is a xylose kinase important in the maturation of proteoglycans. The function of other FAM 20C family members will also be addressed.